7-aminoalkoxy-3-ethyl-2, 3-dihydro-2, 2-dimethyl-1h-benz [e] indes-1-ones and intermediates



Patented Dec. 4, 1962 3,067,207 7-AMINOALKOXY-3-ETHYL2,3-DlHYDRO-2,2-DI- METHYL-IH-BENZ [e] lNDEN-l-ONES AND IN- TERMEDIATESLeland J. Chinn, Morton Grove, Ill., assignor to G. D. Searle & Co.,Chicago, Ill., a corporation of Delaware No Drawing. Filed June 1, 1961,Ser. No. 114,015 6 Claims. (Cl. 260326.5)

This invention relates to 7-aminoalkoxy-3-ethyl-2,3- dihydro-2,2-dimethyl-lH-benz[e]inden-l-ones, intermediates thereto, and themanufacture thereof. More particularly, this invention relates tochemical compounds of the formula Am-Alk-O wherein n represents apositive integer less than 8.

2 wherein m represents a positive integer commonly less than 6.

Equivalent to the hereinabove-described amines for purposes of thepresent invention-are their nontoxic acid addition salts, thecomposition of which is depicted by Am-Alk-O -(H )t wherein Am and Alkhave the meanings previously assigned; X represents one equivalent of ananion-for example, chloride, bromide, iodide, nitrate, phosphate,sulfate, sulfamate, methyl sulfate, ethyl sulfate, benzenesulfonate,toluenesulfonate, acetate, lactate, succinate, malate, maleate,tartrate, citrate, gluconate, asco'rbate, b'enzoate, cinnamate, or thelike which, in combination with the cationic portion of a saltaforesaid, is neither pharmacologically nor otherwise undesirable inphysio- When two alkyl groupings are present, these may be 1 eitherdiscrete, as where Am designates a radical of the v formula orthey maybe joined together directly or through oxygen or a second nitrogen tocompose a radical comprising at least 4 and not more than 7 carbon atomsarranged to form a 5- or 6-membered heterocycle. Such heterocycle, if itcontains oxygen or a second nitrogen (which can 'be substituted by alower alkyl radical) is ordinarily -membered, the oxygen or secondnitrogen beingdisposed para to'the nitrogen attached to the radicalrepresented in the foregoing generic formula by Alk. Examples ofheterocyclic radicals of this type are the morpholino and l-p'iperazinylmoieties.

Illustrative of cyclic amino radicals contemplate by Am, in addition tothe morpholino. and l-piperazinyl groupings named above, areZ-methyl-l-pyrrolidinyl, 2,5- dimethyl1-pyrrolidinyl,2,2,4-trimethyl-l-pyrrolidinyl, 3- methyl-4-ethyl-l-pyrrolidinyl,piperidino, 3-methylpiperi dino, 2,6-dimethylpiperidino,2-methyl-S-ethylpiperidino, 4-methyl-l-piperazinyl,4-ethyl-1-piperazinyl, etc. Among these the l-pyrrolidinyl andpiperidino groupings are radicals of choice, together with the di(loweralkyl) amino groupings previously described. 7

The alkylene radicals represented by Alk in the generic formula are suchas ethylene, trimethylene, propylene, tetramethylene,2-methyl-l,2-propylene, pentamethylene, 2,4-pentylene,2,2-dimethyl-l,3-propylene, and like bivalent saturated acyclicstraightor branched-chain hydrocarbon groupings separating the groupsattached thereto by more than 1 carbon atom and having the formula vmH:m

logical dosage; and 2 represents 1 except when Am comprises 2 nitrogens,in which case t represents a positive integer less than 3.

The compounds to which this invention relates are useful because oftheir valuable pharmacological prop erties. Thus, for example, they areanti-biotics variously effective against bacteria such as Diplococcuspneumoniae, fungi such as Tricophyton mentagrophytes, algae such asChlorella vulgaris, and cotyledenous seed germination. Further, theyinhibit experimentally-induced hypercholesterolemia, .and areanti-arrhythmic agents.

Manufacture of the subject products proceeds by contacting3-(6-methoxy-2-naphthyl)-2,2-dimethylpentanoic acid with hydrogenfluoride to form 3-ethyl-2,3-dihydro-7-methoxy-2,2-dimethyl-1H-benz[e]iden-l-one, which, in turn, is heatedin an inert atmosphere with pyridine hydrochloride to cleave the7-methoxy group. The 3- ethyl-Z,3-dihydro-7-hydroxy-2,2-dimethyl-1Hbenz[e]inden-l-one thus obtained is converted under nitrogen to thesodio derivative by heating with sodium amide in an anhydrous solventsuch as toluene, whereupon a selected haloalkylamine Am-Alk-Cl isintroduced and heating under nitrogen continued to I give the desiredaminoalkoxy base hereof. [Am and Alk in the formula for thehaloalkylamine have the same significance as before] As an exception tothis procedure, 3-ethyl-2,3-dihydro-7-hydroxy-2,Z-dimethyl 1H-benz[e]inden-1-one, .upon being heated with propylene oxide under theinfluence of sodium ethoxide in dioxane solution, is converted to3-ethyl-2,3-dihydro-7-(p-hydroxypropoxy)-2,2-dimethyl 1Hbenz[e]inden-l-one, wherein the hydroxyl is replaced with chlorine oncontact with thionyl chloride catalyzed by pyridine in benzene Theresultant chloro compound affords 3-.

solution. ethyl-2,3-dihydro-2,2-dimethyl-7-(pmethyl-fl-piperidinoethoxy)-lH-benz[e]inden-l-one upon being heated withpiperidine in benzene solution.

The acid addition salts of the disclosed amine bases are obtained simplyby mixing stoichiometric quantities of the bases with any of variousinorganic and strong organic acids in which ,the anionic component canbe represented by X as hereinabove defined.

The following examples describe in detail compounds illustrative of thepresent invention and methods which have been devised for theirmanufacture. However, the invention is not to be construed as limitedthereby, either in spirit or scope, since it will be apparent to thoseskilled in the art of organic synthesis that many modifications,

wise noted.

both of materials and methods, may be practiced with out departing fromthe purpose andintent of this disclo-.

Example 1 A. 3ethyl-2,3-dihydr0 7 methoxy-2,2-dimethyl-IH-benz[e]inden-1-0ne.-A mixture of 25 parts of 3-(6-methoxy-Z-naphthyl)-2,2-dimethylpentanoic acid and 250 parts of hydrogenfluoride is allowed to evaporate to dryness during 17 hours. The residueis taken up in ether. The ether solution is washed successively withwater, aqueous 2% sodium hydroxide, and a saturated aqueous solution ofsodium chloride, whereupon it is dried over anhydrous sodium sulfate andthen stripped of solvent by Vacuum distillation. {The residue thusobtained, crystallized from hexane, affords 3-ethyl-2,3-dihydro-7-methoxy- 2,2fdimethyl-ll lfben zf ei]irid" flone ascolorless rhornbo rolls melun'g at approximately 86-87".

I I ethyl 2,3 dihydrbl ihethoxy-Z,Z-dimethyl-ZH- ben z[e]i1 zder t-' Iorie;--'A mixture of 3 parts of 3-ethyl-2, 3-dihYdrO-Lmthoxy-LZ-dimethyl-1H f ben z[e]indenl-one and 22 parts ofpyridine hydrochloride is. rr iaintained at 2l1 in an-atmosphere ofnitrogenfor arranges, then cooledand triturated with water. Solids arefiltered off, washed with water, and,finally crystallized from aqueousmethanol to afiord 3 'ethyl2;3-dihydro-7-hydroxy2,2-dimethyl-lH-benz[e]inden-l-one as colorless needles melting at156-1602. 7

C. 3-ethyI-7- (Z-diethyIaminoeIhOxy)-2,3-dihydro 2,2-dimethyl-lHvb'enz[e]inden-I-one.--To a solution of 100 parts of3-ethyl-2,3-dihydro-7-hydroxy-2,Z-dimethyl-1H- benz[e]inden-l-one in 900parts of anhydrous toluene is added 17 parts of sodium amide. Theresultant mixture is heated with agitation at the boiling point underreflux in an atmosphere of nitrogenfor 2 hours, then diluted with anadditional 450 parts of anhydrous toluene. A solution of 60 parts of2-diethylaminoethyl chloride in 90 parts of anhydrous toluene isthereupon slowly introduced, following which heating at the boilingpoint under reflux in a nitrogen atmosphere is resumed for 17 hours. Anequal volume of water is then mixed in and the toluene phase separatedand washed successively with aqueous 5% sodium hydroxide, water, and asaturated aqueous sodium chloride solution. Dried over anhydrous sodiumsulfate and stripped. of solvent by vacuum distillation, the toluenesolution affords a viscous brown residue3-ethyl-7-(2-diethylamiuoethoxy)-2,3-dihydro-2,2-dimethyl-lH-benz [e]-inden-l-one. The product has the formula zNCHzCEzO Example 23-ethyl-2,3-dihydro 2,2 dimethyl-7-(w-dz'methylaminopentoxy)-1H-benz[e1inden-1-one.-Substitution of 66 4 partsof5-dimethylaminopentyl chloride for the Z-diethylaminoethyl chloridecalled for in Example 10 affords, by the procedure there detailed,3-ethyl-2,3-dihydro-2,2-dimethyl 7(w-dimethylaminopentoxy)-1H-benz[e]indenl-one of the formula CHs C2Hu (Ca)2N( 2)sO Example 3 A. 3 ethyl 2,3 dihydro 2,2 dimethyl 7-[6-(1-pyrr0Iidinyl)eth0xy]-1H benz[e]inden-I-one.--Substitution of 60 parts of2-( l-pyrrolidinyl)ethyl chloride for the 2-diethylaminoethyl chloridecalled for in Example 10 affords, by the procedure there detailed,3-ethyl-2,3-dihydro-2,2-dimethyl-7-[;3-(1-pyrrolidinyl)ethoxy] lH-benz-[e]inden-1-one as a viscous oil. The product has the formula O- --CH1H-benz[e]inden-l-one hydrochloride as colorless rhomohedrons melting at189-191. I

Example 4 A. 3 ethyl 2,3 dihydro' 7 (fi-hydr0xypropoxy)-2,2-dimethyl-1H-benz[e]inden-1-0ne.-A mixture of parts of3-ethyl-2,3-dihydro-7-hydroxy-2,Z-dimethyl-1H- benz[e]inden-l-one, 2parts of sodium ethoxide, 25 parts of propylene oxide, and 200 parts ofdioxane is maintained at 100 in an autoclave for 15 hours.' Theresultant mixture is cooled and then distilled to dryness in vacuo. Theresidue is partitioned between chloroform and aqueous 5% sodiumhydroxide. The chloroform phase is separated and washed successivelywith water and saturated aqueous sodium chloride. It is then dried overanhydrous sodium sulfate and stripped of solvent by vacuum distillation.The residue is the desired3-ethyl-2,3-dihydro-7-(fihydroxypropoxy)-2,2-dimethyl-1H-benz[e]inden-l-oue.

B. 7 (flc'hloropropoxy) 3 ethyl 2,3 dihydro 2,2-dimethyl-]H-benz[e]inden I-0rte.-To a solution of 100 parts of3-ethyl-2,3-dihydro-7-(fi-hydroxypropoxy)-2,2-dimethyl-lH-benz[e]inden-l-onein 450 parts of benzene at 0-5 is added 164 parts of thionyl chlorideand 2 parts of pyridine. The resultant mixture is let stand at roomtemper'atures for one hour and then stripped of solvent and excessthionyl chloride by vacuum distillation at 30. The residue is7-(fi-chloropropoxy)-3-ethyl-2,3-dihydro-2,2-dimethyl-lH-benz[e]inden-l-one.

C. 3 ethyl 2,3 dihydro 2,2 dimethyl 7 (fimethyl-fi-piperidinoethoxy) 1Hbenz[e]inden-I-one.-- To a solution of 100 parts of7-(fl-chloropropoxy)Ii-ethyl-2,3-dihydro-2,2-dimethyl-lH-benz[elinden-l-one in 450 parts-of benzeneis added 100 parts of piperidine. The resultant mixture is heated at theboiling point under reflux for 2 hours, then cooled and filtered. Thefiltrate, stripped of solvent by vacuum distillation, afiords as theresidue 3- ethyl 2,3 dihydro 2,2 dimethyi 7(p-methyl-flpiperidinoethoxy)-1H-benz[e]inden-l-one, having the formula-C:Hl

CH3$HCHIO What is claimed is: I 1. A compound of the formula wherein Zrepresents a member of the group consisting of 7 amino radicals of theformulas r'r 1 --N(loweralkyl)| U and the alkylene radical called forseparates the groups attached thereto by more. than 1 carbon atom andcontains fewer than 6 carbon atoms.

2. A compound of the formula (lower alkyDzN-allrylene-O wherein thealkylene radical called for separates the groups No references cited.

1. A COMPOUND OF THE FORMULA